The program is designed to prepare the applicant for a productive career as an independent clinician researcher in the field of neurodegenerative disease. This program consists of supervised basic research into the cellular and molecular biology of prion disease, course work on aspects of cell biology and biochemistry, clinical experience in neurologic disorders with an emphasis on neurodegenerative conditions resulting in disorders of movement, and the teaching of residents and medical students. The core of the program consists of a research project designed to explore aspects of prion pathophysiology related to the cell types which generate prions, and the role of interactions between cell types involved in the propagation of prions. Transgenic mice in which ectopic expression of the prion protein (PrP) is directed to specific cell types are being developed. Animals carrying transgenes in which the promoter/enhancer region of a cell type specific gene is linked to a PrP coding sequence will express PrP only in granule cells of the cerebellum, skeletal muscle or beta-cells of the pancreatic islets. These animals will be inoculated with prions and observed for the development of spontaneous disease in order to determine whether multiple cell types are needed to propagate prions in vivo, whether the cell type in which prions are produced influences the strain properties of prions, whether non-neuronal cells can produce prions and, if so, if they are susceptible to prion mediated pathologic changes. These studies may lead to a rapid bio-assay for prions. Observations in these animals may also demonstrate similarities between the mechanism of prion disease and inclusion body myositis or type Il diabetes mellitus. If so, these animals may serve as models of these conditions. The applicant has already developed transgenic lines directing high levels of PrP expression to skeletal muscle and beta-islet cells of the pancreatic islets. Clinical experience will consist of attending in the neurology clinic. Teaching experience will consist of instruction and supervision of residents and medical students in the neurology clinic, presentations at clinical conferences, and preceptoring medical students in the Introductory to Clinical Medicine course.